Pulmonary Arterial Hypertension (PAH) is a life-threatening disease that is significantly more frequent in HIV-infected individuals even with antiretroviral therapy. How HIV contributes to the pathophysiology of HIV-PAH remains unknown. HIV proteins are the main suspects but the exact mechanisms whereby these proteins influence vascular remodeling are unknown. HIV proteins like Tat, Nef and gp120 likely play a role in the pathogenesis of HIV-PAH. HIV gp120 binds to either CCR5 (R5) or CXCR4 (X4) chemokine receptors after interacting with CD4. Either CCR5 or CXCR4-ligand interactions promote inflammation leading to vascular remodeling in animal models of PAH. We have preliminary evidence that HIV-infected individuals with PAH harbor significantly more CXCR4-utilizing HIV variants (X4 viruses). While CCR5 signaling leads to PAH in SIV-infected macaques, our finding of an association between X4 viruses and PAH in HIV-infected individuals lead us to focus specifically on the contribution of X4 viruses to HIV-PAH. Furthermore, we found that HIV-X4, compared to R5 gp120, induces over-expression of the vasoconstrictive arachidonate 5- lipoxygenase (ALOX-5) gene in pulmonary endothelial cells. Hence, our research has uncovered X4 viruses as potential agents in the pathophysiology of HIV-PAH. Whether CXCR4 signaling in the presence of HIV X4 virus leads to PAH remains elusive. We hypothesize that HIV X4 induces chronic inflammation leading to pulmonary vascular remodeling and PAH via CXCR4 signaling. We believe that, in order to advance this field, it is imperative to first validate a model for HIV-PAH and examine the impact of X4 viruses on the pulmonary vasculature. Unfortunately, other than non-human primates, there is no HIV-PAH animal model that recapitulates the natural history of this disease. To test our hypothesis, we propose to validate the state-of-the- art mice engrafted with human Bone marrow, Lymph node and Thymus (hu-BLT) as model for HIV-PAH. APPROACH: We propose to: 1) characterize pulmonary vascular remodeling and right ventricular hypertrophy in HIV-infected hu-BLT mice, and 2) examine the functional role of CXCR4 signaling in pulmonary vascular cells exposed to HIV X4 virus in vivo and in vitro. SIGNIFICANCE AND INNOVATION: These studies are significant because our model will accelerate mechanistic studies on the CXCR4 signaling pathway that may allow for convergent mechanistic explanations for other forms of PAH, e.g. idiopathic and hypoxia-induced PAH, and will help explain why HIV patients are more prone to vascular diseases affecting other end-organs like kidneys and brain. In addition, we bring the innovative theoretical concept that CXCR4-utilizing HIV plays a role in PAH and pioneer the hu-BLT mouse to gain insights into HIV-associated pulmonary vasculopathy.